Latent class model with familial dependence to address heterogeneity in complex diseases: adapting the approach to family-based association studies

Abstract

Clinical diagnoses of complex diseases may often encompass multiple genetically heterogeneous disorders. One way of dissecting this heterogeneity is to apply latent class (LC) analysis to measurements related to the diagnosis, such as detailed symptoms, to define more homogeneous disease sub-types, influenced by a smaller number of genes that will thus be more easily detectable. We have previously developed a LC model allowing dependence between the latent disease class status of relatives within families. We have also proposed a strategy to incorporate the posterior probability of class membership of each subject in parametric linkage analysis, which is not directly transferable to genetic association methods. Under the framework of family-based association tests (FBAT), we now propose to make the contribution of an affected subject to the FBAT statistic proportional to his or her posterior class membership probability. Simulations showed a modest but robust power advantage compared to simply assigning each subject to his or her most probable class, and important power gains over the analysis of the disease diagnosis without LC modeling under certain scenarios. The use of LC analysis with FBAT is illustrated using autism spectrum disorder (ASD) symptoms on families from the Autism Genetics Research Exchange, where we examined eight regions previously associated to autism in this sample. The analysis using the posterior probability of membership to a LC detected an association in the JARID2 gene as significant as that for ASD (p = 3×10−5) but with a larger effect size (odds ratio = 2.17 vs. 1.55).

Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability

“…Loss of function mutations in the lysine-specific demethylase JARID1C , another gene of the JARID family, also causes syndromic intellectual disability (MIM 300534). In addition, two studies have shown association between JARID2 and ASDs, when using the data from the Autism Genetic Resource Exchange (AGRE) [38,39]. Based on these observations, we suggest that JARID2 is likely to be the critical gene within SRO I, and the main gene causing the neurodevelopmental syndrome in Patients 1–4.…”

Efficacy and safety of Fufangkushen colon-coated capsule in the treatment of ulcerative colitis compared with mesalazine: A double-blinded and randomized study

“…LCA is employed in the indications exploration, which can facilitate targeting future intervention resources to subgroups that promise to show the maximum treatment response (Bureau et al, 2011;Lanza and Rhoades, 2011). Traditionally, subgroup analysis aims to determine whether individuals respond differently to a treatment based on one or more measured characteristics.…”

Family-Based Association Analysis of Alcohol Dependence Criteria and Severity

“…As a result, information describing each latent class provided an interpretation of the three classes while the probability of being in each class was employed as the phenotype in analysis. This approach avoids multiple pairwise comparisons of the three classes in analyses, avoids misclassification inherent in assigning individuals to a particular latent class, maximizes the number of subjects, and was shown previously to improve power to detect genetic association (Bureau et al, 2011). …”